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Cytochrome P450 Oxidation of the Thiophene-Containing Anticancer Drug 3-[(Quinolin-4-ylmethyl)-amino]-thiophene-2-carboxylic Acid (4-Trifluoromethoxy-phenyl)-amide to an Electrophilic Intermediate

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Drug Metabolism and Pharmacokinetics, OSI Pharmaceuticals, Boulder, Colorado 80301
* To whom correspondence should be addressed. Drug Metabolism and Pharmacokinetics, OSI Pharmaceuticals, Inc., 2860 Wilderness Place, Boulder, CO 80301. E-mail: [email protected]
†Present address: DMPK and Bioanalytical Services, ABC Laboratories, Inc., 7200 E. ABC Lane, Columbia, MO 65202.
‡Present address: Tucson, AZ.
Cite this: Chem. Res. Toxicol. 2008, 21, 8, 1570–1577
Publication Date (Web):August 2, 2008
https://doi.org/10.1021/tx700430n
Copyright © 2008 American Chemical Society
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    Abstract

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    Compounds that are enzymatically transformed to reactive intermediates are common in nature. Some drugs and many phytochemicals that contain a thiophene ring are oxidized by cytochrome P450 to biological reactive intermediates (BRI) that can covalently bind to thiol nucleophiles. The investigational anticancer agent 3-[(quinolin-4-ylmethyl)-amino]-thiophene-2-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (OSI-930) contains a thiophene moiety that can be oxidized by P450s to an apparent sulfoxide, which can react via Michael-addition to the 5-position of the thiophene ring, as demonstrated by mass spectral characterization of several thioether conjugates of the presumed thiophene S-oxide. Furthermore, a stable deuterium isotope retention experiment in which solvent deuterium was incorporated into the thiophene verifies the sulfoxide pathway. Various thiol nucleophiles are shown by tandem mass spectra to bind with this BRI, which is activated by P450 3A4 and to a slight degree, P450 2D6. Yet various safe drugs, phytochemicals, and endogenous molecules, all noted for their activation to BRI, are not toxic at a normal dose. Thus, multiple features determine any consequence of a BRI, with these complexities determining why one BRI is benign while another is not. The retention of covalent protein adducts of radio-labeled intermediate rat tissue has a half-life of about 1−1.5 days; hence, modified protein is cleared and replaced relatively quickly.

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    Results of in vivo protein covalent bonding of radio-labeled drug equivalent and clearance over a week. This material is available free of charge via the Internet at http://pubs.acs.org.

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